This invention relates to carbocyclic analogues of amino and azido thymidines and to the use of such compounds in the treatment of viral infections.
The term "carbocyclic analogue of a nucleoside" designates a compound that has the same chemical structure as the nucleoside except that the oxygen atom of the furanose moiety of the nucleoside is replaced by a methylene group in the carbocyclic analogue; or, differently expressed, in the carbocyclic analogue a cyclopentane ring replaces the tetrahydrofuran ring of the analogous nucleoside. Such nucleoside analogues were designated carbocyclic analogues of nucleosides by Shealy and Clayton, Journal of the American Chemical Society, Volume 88, pages 3885-3887, 1966. The natural nucleosides and many of their true nucleoside analogues are subject to the action of enzymes (phosphorylases and hydrolases) that cleave the nucleosides to the pentose and purine or pyrimidine moieties. For example, it has been reported by C. Desgranges et al. (Biochemical Pharmacology, Vol. 32, pages 3583-3590, 1983) that various 5-substituted-2'-deoxyuridines including 5-ethyl-2'-deoxyuridine (EDU) and 5-[(E)-2-(bromovinyl)]-2'-deoxyuridine (BVDU) are substrates for thymidine phosphorylase isolated from human blood platelets. The biological effects of such true nucleoside analogues may be lessened by the action of these degradative enzymes. In contrast, carbocyclic analogues of nucleosides do not possess the glycosidic bond present in the true nucleosides and, therefore, are not subject to the action of these degradative enzymes. They may also be more selective in their biological actions.
5'-Amino-5'-deoxythymidine (Chart I, Compound 1, 5'-amino-5'-dThd) and the 5'-azido derivative (Compound 2) were synthesized initially by Horwitz et al (J. Org. Chem., 1962, 27, 3045-3048). Subsequent studies have shown that 5'-amino-5'-dThd is a good inhibitor of thymidine kinase from tumor cells (Neenan et al, J. Med. Chem., 1973, 16, 580-581 and Cheng et al, Biochemistry, 1974, 13, 1179-1185) and a weak inhibitor of thymidylate kinase (Cheng et al, Biochemistry, 1973, 12, 2612-2619); that it is phosphorylated to the 5'-N-diphosphate in cells infected with type 1 herpes simplex virus (HSV-1), but not by a mixture of thymidine kinase and thymidylate kinase from uninfected mammalian cells (Chen et al, Antimicrob. Agents Chemother., 1980, 18, 433-436); and that its 5'-N-triphosphate is incorporated into DNA (Letsinger et al, J. Am. Chem. Soc., 1972, 94, 292-293). 5'-Amino-5'-dThd is a selective inhibitor of HSV-1 replication in cultured cells, but it is not an effective inhibitor of mouse neoplastic cells (L1210 leukemia and Sarcoma 180) (Lin et al, J. Med. Chem., 1976, 19, 495-498 and Lin et al, J. Med. Chem., 1978, 21, 109-112). In contrast, 3'-amino-3'-deoxythymidine (Miller et al, J. Org. Chem., 1964, 29, 1772-1776 and Horwitz et al, J. Org. Chem., 1964, 29, 2076-2078) (Chart I, Compound 3, 3'-amino-3'-dThd) has only slight antiviral activity (Lin et al, J. Med. Chem., 1978, 21, 109-112), but it has potent activity against L1210 leukemia (Lin et al, J. Med. Chem., 1978, 21, 109-112), sarcoma 180 (Lin et al, J. Med. Chem., 1978, 21, 109-112), and P815 mouse leukemia (Matsuda et al, J. Org. Chem., 1980, 45, 3274-3278) cells in culture (ED.sub.50 =1 .mu.M, 5 .mu.M, 0.08 mcg/mL, respectively). In tests against L1210 leukemia in vivo, Lin et al (Biochem. Pharmacol., 1982, 31, 125-128) showed that 3'-amino-3'-dThd can increase markedly the survival times of treated mice, and Chen et al (Molecular Pharmacol., 1984, 25, 441-445) also presented evidence that inhibition of the DNA polymerase reaction is a major site of the inhibitory effects of 3'-amino-3'-dThd.
Following is Chart I: ##STR2##